Gene expression profiling of changes induced by maternal diabetes in the embryonic heart

Bohuslavová, Romana; Skvorova, Lada; Čerychová, Radka; Pavlínková, Gabriela

doi:10.1016/j.reprotox.2015.06.045

Cited by 9 publications

(9 citation statements)

References 61 publications

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“…The main affected systems and anatomical regions are the CNS, craniofacial structures, cardiovascular system, and skeletal system (Zhao & Reece, ). The anomalies occur through different cellular mechanisms as an increase in cellular apoptosis, stress in the endoplasmic reticulum, oxidative stress, and changes in the expression of time‐specific embryonic genes (Bohuslavova, Skvorova, Cerychova, & Pavlinkova, ; Phelan, Ito, & Loeken, ; Wu et al, ). Although the effects produced by the disrupted mechanisms are temporary and dependent on the maternal hyperglycemia peaks, they can be sufficient to cause permanent and irreversible changes in the fetal morphogenesis due to the changes in gene expression, as if the gene has been mutated or deleted (Bohuslavova et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…The anomalies occur through different cellular mechanisms as an increase in cellular apoptosis, stress in the endoplasmic reticulum, oxidative stress, and changes in the expression of time‐specific embryonic genes (Bohuslavova, Skvorova, Cerychova, & Pavlinkova, ; Phelan, Ito, & Loeken, ; Wu et al, ). Although the effects produced by the disrupted mechanisms are temporary and dependent on the maternal hyperglycemia peaks, they can be sufficient to cause permanent and irreversible changes in the fetal morphogenesis due to the changes in gene expression, as if the gene has been mutated or deleted (Bohuslavova et al, ). If a gene is expressed in the mesenchyme of structures such as limb bud, and craniofacial structures, for instance SHH (Sonic Hedgehog) , MSC1 (Meiotic Sex Chromosome Inactivation) , FGF8 (Fibroblast Growth Factor 8), and BMPs (Bone Morphogenetic Proteins), and the disrupted mechanism interferes with the gene expression, the outcome will be morphological changes in both structures (Al‐Qattan, ; Minoux & Rijli, ).…”

Section: Discussionmentioning

confidence: 99%

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Femoral‐facial syndrome: A review of the literature and 14 additional patients including a monozygotic discordant twin pair

Lacarrubba-Flores

Carvalho

Ribeiro

et al. 2018

American J of Med Genetics Pt A

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Femoral-facial syndrome (FFS, OMIM 134780), also known as femoral hypoplasia-unusual face syndrome, is a rare sporadic syndrome associated with maternal diabetes, and comprising femoral hypoplasia/agenesis and a distinct facies characterized by micrognathia, cleft palate, and other minor dysmorphisms. The evaluation of 14 unpublished Brazilian patients, prompted us to make an extensive literature review comparing both sets of data. From 120 previously reported individuals with FFS, 66 were excluded due to: not meeting the inclusion criteria (n = 21); not providing sufficient data to ascertain the diagnosis (n = 29); were better assigned to another diagnosis (n = 3); and, being fetuses of the second trimester (n = 13) due to the obvious difficult to confirm a typical facies. Clinical-radiological and family information from 54 typical patients were collected and compared with the 14 new Brazilian patients. The comparison between the two sets of patients did not show any relevant differences. Femoral involvement was most frequently hypoplasia, observed in 91.2% of patients, and the typical facies was characterized by micrognathia (97%), cleft palate (61.8%), and minor dysmorphisms (frontal bossing 63.6%, short nose 91.7%, long philtrum 94.9%, and thin upper lip 92.3%). Clubfoot (55.9%) was commonly observed. Other observed findings may be part of FFS or may be simply concurrent anomalies since maternal diabetes is a common risk factor. While maternal diabetes was the only common feature observed during pregnancy (50.8%), no evidence for a monogenic basis was found. Moreover, a monozygotic discordant twin pair was described reinforcing the absence of a major genetic factor associated with FFS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Femoral‐facial syndrome: A review of the literature and 14 additional patients including a monozygotic discordant twin pair

Lacarrubba-Flores

Carvalho

Ribeiro

et al. 2018

American J of Med Genetics Pt A

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“…Since it was shown that the kinetics of HIF-1α in response to hypoxia differ between individual organs in adult mice ( 84 ), different organs should be studied separately. Another complication for the understanding of pathologies associated with deregulated HIF-1 signaling during embryonic development is represented by rapid changes in gene expression in different developmental stages ( 85 , 86 ).…”

Section: Diabetic Embryopathymentioning

confidence: 99%

HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart

2018

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The heart is able to metabolize any substrate, depending on its availability, to satisfy its energy requirements. Under normal physiological conditions, about 95% of ATP is produced by oxidative phosphorylation and the rest by glycolysis. Cardiac metabolism undergoes reprograming in response to a variety of physiological and pathophysiological conditions. Hypoxia-inducible factor 1 (HIF-1) mediates the metabolic adaptation to hypoxia and ischemia, including the transition from oxidative to glycolytic metabolism. During embryonic development, HIF-1 protects the embryo from intrauterine hypoxia, its deletion as well as its forced expression are embryonically lethal. A decrease in HIF-1 activity is crucial during perinatal remodeling when the heart switches from anaerobic to aerobic metabolism. In the adult heart, HIF-1 protects against hypoxia, although its deletion in cardiomyocytes affects heart function even under normoxic conditions. Diabetes impairs HIF-1 activation and thus, compromises HIF-1 mediated responses under oxygen-limited conditions. Compromised HIF-1 signaling may contribute to the teratogenicity of maternal diabetes and diabetic cardiomyopathy in adults. In this review, we discuss the function of HIF-1 in the heart throughout development into adulthood, as well as the deregulation of HIF-1 signaling in diabetes and its effects on the embryonic and adult heart.

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“…Additionally, fluctuations in glucose levels (in particular hyperglycemia and hypoglycemia) resulting from maternal diabetes can alter VEGF expression (Oltmanns et al, 2008). Studies have confirmed the teratogenic effects of both hyper-and hypoglycemia (Corrigan et al, 2009;ter Braak et al, 2002;Bohuslavova et al, 2015;Helle et al, 2018), and the role of VEGF in hyperglycemia-induced abnormal cardiovascular development (Kumar et al, 2008;Pinter et al, 2001). Epidemiological studies further reveal that maternal hyperglycemia even in mothers with no diabetes are associated with a 3-5 fold increase in CHD incidence in offspring (Øyen et al, 2016;Basu & Garg, 2018;Priest et al, 2015).…”

Section: Introductionmentioning

confidence: 94%

Transient increase in VEGF‐A leads to cardiac tube anomalies and increased risk of congenital heart malformations

Rykiel

Gray

Rongish

et al. 2021

The Anatomical Record

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Vascular endothelial growth factor (VEGF) plays a critical role during early heart development. Clinical evidence shows that conditions associated with changes in VEGF signaling in utero are correlated with an increased risk of congenital heart defects (CHD) in newborns. However, how malformations develop after abnormal VEGF exposure is unknown. During embryogenesis, a primitive heart, consisting of an endocardial tube enveloped by a myocardial mantle, is the first organ to function. This tubular heart ultimately transforms into a four-chambered heart. To determine how a transient increase in VEGF prior to heart tube formation affects heart development leading to CHD, we applied exogenous VEGF or a control (vehicle) solution to quail embryos in ovo at Hamburger-Hamilton (HH) stage 8 (28-30 hr of incubation), right before heart tube formation. Light microscopy analysis of embryos reincubated after treatment for 13 hrs (to approximately HH11/HH12) showed that increased VEGF leads to impaired heart tube elongation accompanied by diameter expansion. Micro-CT analysis of embryos re-incubated for 9 days (to approximately HH38), when the heart is fully formed, showed that VEGF treatment increased the rate of cardiac malformations in surviving embryos.Despite no sex differences in survival, female embryos were more likely to develop cardiac malformations. Our results further suggest that heart tube malformations after a transient increase in VEGF right before heart tube formation may be reversible, leading to normal hearts.

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Gene expression profiling of changes induced by maternal diabetes in the embryonic heart

Cited by 9 publications

References 61 publications

Femoral‐facial syndrome: A review of the literature and 14 additional patients including a monozygotic discordant twin pair

Femoral‐facial syndrome: A review of the literature and 14 additional patients including a monozygotic discordant twin pair

HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart

Transient increase in VEGF‐A leads to cardiac tube anomalies and increased risk of congenital heart malformations

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